title: Phosphodiesterase-2 is up-regulated in human failing hearts and blunts β-adrenergic responses in cardiomyocytes.
abstract: OBJECTIVE
  This study investigated whether myocardial phosphodiesterase-2 (PDE2) is altered in heart failure (HF) and determined PDE2-mediated effects on beta-adrenergic receptor (β-AR) signaling in healthy and diseased cardiomyocytes.
  
  
  BACKGROUND
  Diminished cyclic adenosine monophosphate (cAMP) and augmented cyclic guanosine monophosphate (cGMP) signaling is characteristic for failing hearts. Among the PDE superfamily, PDE2 has the unique property of being able to be stimulated by cGMP, thus leading to a remarkable increase in cAMP hydrolysis mediating a negative cross talk between cGMP and cAMP signaling. However, the role of PDE2 in HF is poorly understood.
  
  
  METHODS
  Immunoblotting, radioenzymatic- and fluorescence resonance energy transfer-based assays, video edge detection, epifluorescence microscopy, and L-type Ca2(+) current measurements were performed in myocardial tissues and/or isolated cardiomyocytes from human and/or experimental HF, respectively.
  
  
  RESULTS
  Myocardial PDE2 expression and activity were ~2-fold higher in advanced human HF. Chronic β-AR stimulation via catecholamine infusions in rats enhanced PDE2 expression ~2-fold and cAMP hydrolytic activity ~4-fold, which correlated with blunted cardiac β-AR responsiveness. In diseased cardiomyocytes, higher PDE2 activity could be further enhanced by stimulation of cGMP synthesis via nitric oxide donors, whereas specific PDE2 inhibition partially restored β-AR responsiveness. Accordingly, PDE2 overexpression in healthy cardiomyocytes reduced the rise in cAMP levels and L-type Ca2(+) current amplitude, and abolished the inotropic effect following acute β-AR stimulation, without affecting basal contractility. Importantly, PDE2-overexpressing cardiomyocytes showed marked protection from norepinephrine-induced hypertrophic responses.
  
  
  CONCLUSIONS
  PDE2 is markedly up-regulated in failing hearts and desensitizes against acute β-AR stimulation. This may constitute an important defense mechanism during cardiac stress, for example, by antagonizing excessive β-AR drive. Thus, activating myocardial PDE2 may represent a novel intracellular antiadrenergic therapeutic strategy in HF.
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France; Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Hind
authors.initials: H
authors.lastname: Mehel
authors.forename: Julius
authors.initials: J
authors.lastname: Emons
authors.forename: Christiane
authors.initials: C
authors.lastname: Vettel
authors.forename: Katrin
authors.initials: K
authors.lastname: Wittköpper
authors.forename: Danilo
authors.initials: D
authors.lastname: Seppelt
authors.forename: Matthias
authors.initials: M
authors.lastname: Dewenter
authors.forename: Susanne
authors.initials: S
authors.lastname: Lutz
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Patrick
authors.initials: P
authors.lastname: Lechêne
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leroy
authors.forename: Florence
authors.initials: F
authors.lastname: Lefebvre
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vandecasteele
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D002478:Cells, Cultured; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000096:biosynthesis* / Q000502:physiology; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human
keywords: ANP; Ad-βGal; B-type natriuretic peptide; BAY; BAY 60-7550; BNP; EGF; FRET; HF; I(Ca,L); ISO; L-type Ca(2+) current; LV; NO; PDE2; SNP; adenovirus encoding β-galactosidase; atrial natriuretic peptide; beta-adrenergic receptor; cAMP; cGMP; cyclic adenosine monophosphate; cyclic guanosine monophosphate; fluorescence resonance energy transfer; green fluorescent protein; heart failure; isoprenaline; left ventricular; nitric oxide; phosphodiesterase 2; phosphodiesterase-2; sodium nitroprusside; β-AR; β-adrenoceptor signaling